M . USKOKOVIC, H . BRUDERER, C. VON PLASTA,T. WILLIAMS, A N D A. BROSSI
33 64
[CONTRIBUTION FROM T H E
RESEARCHLABORATORIES, HOFFMANN-LA ROCHE I X C . , X U T L E Y 10, N. J . , A S D CO., AG., BASLE,SKITZERLAND]
AND
Vol. 86
F, HOFFMANN-LA ROCHE
The Nuclear Magnetic Resonance Spectra of the Angular Proton in Benzo[a]- and Indolo [a]quinolizidines' BY 11.U S K O K O V I 6 , ' H. BRUDERER,3c. VON
PLXriTAk,3T. \vILLIAMS,* A N D
A. BROSSI~
RECEIVED MARCH19, 1964
A general method for assigning conformational structures t o benzo[a]quinolizidines is presented with several substituted benzo [e]quinolizidines serving as examples. T h e angular proton of trans conformers resonates a t a field higher than 6.2 7 , whereas both c i s conformations are characterized by a downfield signal below 6.2 T . I t is possible, furthermore, to distinguish between the two alternative cis forms by t h e splitting pattern of t h e angular proton. I n one cis form, the angular proton is gauche ( a e ) to one adjacent methylene proton and trans-diaxial to the other, and shows a quartet with srnall ae ( J = 5 c . P . s . ) and large aa ( J = 11 c . P . s . ) splittings, i , e . , roughly a 1: 1 : 1 : 1 quartet. I n the alternative cis form, the angular proton is gauche to both adjacent methylene protons, and shows a quartet with the inner lines close together, i.e., roughly a 1 : 2 : 1 triplet, since ae a n d ee splittings are generally equal in magnitude.
The quinolizidine ring system is a structural feature common to many natural products. Quinolizidjne itself can exist in two all-chair conformations. The preferred conformation4 I has the two rings trans fused, with the hydrogen atom a t '2-10 trans-diaxial to the lone electron pair of the tertiary nitrogen atom. In the less favored conformation 11, the two rings are cis fused, and the hydrogen atom a t C-10 is gauche to the lone electron pair.
H
In simply substituted quinoli~idines~ or larger molecules containing a quinolizidine moiety, such as benzo[a ]quinolizidines and indolo [a]quinolizidines, one trans form and two cis forms should be considered. In the two possible all-chair cis forms, the angular hydrogen is oriented differently with respect to the rings. In the benzo [a]quinolizidine (IV), the 1lb-hydrogen is pseudoequatorial to ring B and axial to ring C, whereas in V, it is pseudo-axial to ring B and equatorial to ring C.
I11
IV
f N-H
VI
VI1
q V
VI11
(1) Presented a t t h e 14;lth h-ational l l e e t i n g of t h e American Chemical S o c i e t y , N e w V o r k , K Y , S e p t . , 1963, A b s t r a c t s of P a p e r s , p Z l Q . ( 2 ) Hoffmann-La R o c h e , I n c , N u t l e y 10, N J. ( 3 ) F Hoffmann-La Roche a n d Co , AG. Basle, Switzerland. (4) T . 11.l f o y n e h a n . K . Schofield. I 1 A . Y. Jones, a n d A R. K a t r i t z k y , J . Chem Soc., 2637 ( 1 9 6 2 ) : 4 . R K a t r i t z k y , Record C h e m . P V O R YZ3, , 223 (1'362)
Similarly, in indolo [aIquinolizidine (VII), the 3hydrogen is pseudo-equatorial to ring C and axial to ring D, whereas in VIII, i t is pseudo-axial to ring C and equatorial to ring D. The first spectroscopic criterion utilized to distinguish the trans-quinolizidines from cis-quinolizidines was the presence or absence of "Bohlmann bands"j in their infrared spectra. Solutions of trans-quinolizidines, in which the lone electron pair on the nitrogen is trans-diaxial to a t least two hydrogens on adjacent carbon atoms, show prominent infrared bands between 2700 and 2800 cm.-'. Such a relationship of the electron pair t o two hydrogens is not possible in cisquinolizidines, and these infrared bands are not found in their spectra. This method had been applied successfully in the structural assignment of many natural and synthetic products. In some cases, the low intensity of these bands makes the method less reliable.6 Katritzky and co-workers,*in addition to using the Bohlmann bands, have used n.m.r. to differentiate between trans- and cis-quinolizidines in the case of methyl derivatives. They observed that, in a series of N-methylquinolizidinium cations, the +N-methyl protons of rnethiodides with cis-fused rings absorbed a t lower fields than those of trans-fused analogs. In a series of yohimbine alkaloids,' the +X-CHz peak in a cis-fused N-methylquinolizidinium system appeared near 6.5 T , while the corresponding peak in the trans fused series showed up near 6.7 T . The same relationship was also found for the heteroyohimbine alkaloid methiodides. In another development, Rosen and Shoolery* observed that in the case of methyl reserpate ( I X ) , corresponding to the partial cis formula VIII, the angular proton a t C-3 resonated a t a field lower than 6.2 T . In methyl neoreserpate ( X ) , corresponding to the partial trans formula VI, the angular proton absorbed a t 6.8 T . ~\Venkert and co-workerslo found ( 5 ) F. B o h l m a n n , Alipeu, C h e m , 69, 611 (1957); Chem. B e ? , 9 1 , 2157 (1958); E. Lt'enkert a n d D. K . R o y c h a u d h u r i , J . A m Chem Soc , 78, 6417 ( I W S ) , \V. E Rosen, l'elraheiii,on I , r l l e r s , 481 (1961) (6) L . BlahaB, B K a k b f , a n d J . Weichet, Colleclion Czech. Chem. C o w mi^^, 27, 857 ( l Y 6 2 ) , T T a k e m o t o , Y . K o n d o , a n d K . K o n d o , J . Phnrm S o c J o p n i z . 83, 162 (1963) ( 7 ) 51 S h a m m a a n d J Sf R i c h e y , J , A m . Chem Soc , 86, 2507 (1963) (8) 1%' E Rosen, 7'elraheJron L e l l r i s , 481 (1'261); W. E Rosen a n d J S Shoolery. J A m C h r m S O L ,83,1816 (1961). (9) ll X I Ilohison, IV G . Pierson. K A . L u c a s , I. H a u , a n d R 1, Dzienian, J O i g . C h e m , 28, 768 (1968). (IO) E TTenkert. B \Tickberg, a n d C L. L e i c h t , J . A m C'hrm. Soc., 83, ,7037 (1961); T e t r a h e d r o n L e l l e r s , 8 2 2 (1961).
Aug. 20, 1964
N.M.R.O F
I
3365
ANGULAR P R O T O S I N [U]QUINOLIZIDINES
I
I,
2
3
4
5
7
6
8
9
10
Fig. 1.--N.m.r. spectrum of trons-2-(~-chlorophenyl)-1,2,3,4,6,7-hexah~dro-llbH-benzo[a] quinolizine ( X I )
a similar difference in the n.m.r. spectra of heteroyohimbine alkaloids : 3-isoajmalicine, corresponding to the partial cis formula VIII, gave a signal for the C-3 proton at 5 . 5 5 T , whereas the C-3 proton of ajmalicine, which belongs to the trans series VI, resonated a t higher fields. We have now found that this difference in chemical shifts for the angular proton is much more general: i t also occurs in benzo[a]quinolizidines, and a low field signal below 6.2 T is characteristic for both cis conformations. It is possible, furthermore, to distinguish between the two alternative cis forms by the splitting
a quartet with the inner lines close together, i e . , roughly a 1 :2 : 1 triplet, since ea and ee splittings are, in general, equal in magnitude. Inspection of the n.m.r. spectra of the compounds shown in Chart I makes these relationships clear. The conformations shown in this chart are supported by the infrared spectra and by inspection of their molecular models.
gQeC CHARTI
/
\
XI11
x
oca
XI
\
XI1
OCH3 XIV
pattern of the angular proton. The angular proton of the cis forms IV and VI1 is gauche (ae) to one adjacent methylene proton and trans diaxial (aa) to the other, and should show a quartet with small ae ( J = 2-5 c.P.s.) and large a a ( J = 9-12 c . P . s . ) ~splittings, ~ i.e., roughly a 1 : I : I:1 quartet. In the alternative cis forms V and VIII, the angular proton is gauche to both adjacent methylene protons, and should show
",
,e
e**
I/
4'
I-
1
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pa-] 8,
+Jae+
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'.
+Jae+ #,
',
,*' '
'y''i
'.
+JWd
(11) A . C . Huitric, J. B. Carr, W. F.Trager, and 19, 2145 (1963).
+Jee+
B. J. Nist, T e t r a h e d r o n ,
Compounds X I and XI11 show Bohlmann bands a t 2755, 2805 cm.-' and 2755, 2795 cm.-', respectively. The n.m.r. spectra (Fig. 1 and 3) show no downfield one-proton signal below 6.2 T attributable to the angular 1lb-proton. These compounds are examples of the trans form 111. Their isomers X I 1 and X I V show no Boh!mann bands. Compound X1V shows (Fig. 4) a downfield one-proton signal centered a t 6 T , the triplet ( J = 5
M. USKOKOVI~, H. BRUDERER, C. VON PLASTA,T. WILLIAMS, A N D A. BROSSI
3366
VOl. 86
Fig. 2.--S m . r . spectrum of c~s-2-(~-chlorophenyl)-1,2,3,4,6,7-hexahydro-llbH-benzo[a]~uinolizine IXII)
I
F-
\l.?
I . .
,
,
2
I . , , . , .
I
,
4
3
Fig. 3.--S.rn.r.
.
, . ,
, I .
I
l . . . , , . . , . I , .
5
6
7
,
I . . ,
I
.
,
Q
8
,
.
I10
spectrum of Irans-2-(p-chlorophenyl)-Q,lO-dimethoxy-1,2,3,4,6,7-hexahydro-llbH-benzo[a]quinolizine (XIII).
t I
7f
1
I
2
Fig
4 --N
I
1
3
4
5
6
7
8
9
10
rn r spectrum of cis-2-(~-chloropheny1)-9,10-dimethoxy-1,2,3,4,6,7-hexah~dro-llbH-benzo[a]quinolizine (XIV)
N.M.R.OF ANGULARP R O T O N IN
Aug. 20, 1964
I I . . . . , , .
2
Fig 5 --N
I . . . . # . , . . l . .
3
4
. #
,
I .
,
I
5
1
6
,
I
,
.
3367
[a]QUINOLIZIDINZS
1 ,
7
.
1
,
.
I . ,
8
,
,
,
, ,
9
10
m.r. spectrum of 2-keto-4,4-dimethyl-9,l0-ditnethoxy-1,2,3,4,6,7-hexahydro-llbH-benzo[~]quinolizine (XV)
c.P.s.) structure of which is partly masked b y the peaks due to the methoxy groups. However, in the nonmethoxylated analog X I I , the angular proton a t C - l l b appears clearly (Fig. 2 ) as a 1 : 2 : 1 triplet centered a t 6 T with J = 5 C.P.S. These two conipounds are examples of the cis form V. T h e ketone X V shows no Bohlmann bands. It is an example of the alternative cis form I V : its angular proton a t C-1l b gives rise to a 1: 1 : 1: 1 quartet centered a t 5.85 T with splittings Jae= 5 C.P.S. and Jaa= 11 C.P.S. (Fig. 5 ) . These differences observed in the chemical shift could be largely due to the relationship of the angular proton with respect t o the lone electron pair of the nitrogen. If the longitudinal magnetic susceptibility of the lone pair is larger than the transverse susceptibility, as for a carbon-carbon triple bond,'* an angular proton gauche to the pair would be deshielded, whereas (12) L M J a c k m a n n , "Applications of Nuclear M a g n e t i c R e s o n a n c e X Y , S p e c t r o s c o p y i n Organic C h e m i s t r y , " P e r g a m o n Press, Y e w York, i 1939, p p 113-119
an angular proton trans-diasial to the pair would be shielded, Experimental T h e infrared spectra were determined with solutions in chloroform, on t h e Beckrnan IR-9 spectrometer. The proton n.m.r. spectra were determined on a n A-60 \'arian spectrometer, with solutions in deuteriochloroform. T h e chemical shifts are espressed a s 7 units, and are referred to T M S as the iiiteriial reference. T h e syntheses of: trans-2-(p-cliloropIieiiyl)-l,2,~,4,6,7hexahydro-llbH-benzo[a]quinolizine ( X I ) , czs-2-(p-clilorophenyl)-l,2,3,4,6,7-hexaliydro-llbH-benzo [a] quitiolizine ( S I I ), Irons-
2-(p-chlorophenyl)-9,l0-dirnetlioxy-l,2,3,4,6,~-Iie~;i1iS.dro-llbHquinolizine ( X I I I ) and cis-2-(p-cliloropl1e1i~l)-9,ll~-dirnethoxy-1,2,3,4,6,7-hexahydro-llbH-beiizo[n] quiiioliziiie (SI\.) lvere reported recently b y o u r group.13 Coinpounds XI11 aiid X I I had already been prepared by other i ~ i e t h o d s . T ~ h~e synthesis of 2-keto-4,4-dimethyl-9,10-ditnethosy-l,2,3,4,B,~-liexaliy~~ro-llbH-benzo[a] quinolizine ( X V ) has beeti reported by Beke and SzBntay.15 (13) H. Bruderer, M . B a u m a n n , M UskokoviC, a n d A . Brossi, A h s t r a c t s , 147th S a t i o n a l M e e t i n g of American Chemical Society, P h i l a d e l p h i a , Pa , April, 1964 C o m p l e t e details will he published soon in H ~ l i j ,C h i m A r l n (14) J . Gootjes a n d W . T h . N a u t a , Rec. L ~ a u chim , 80, 1223 (1'361) (15) D. Beke a n d C. S z l n t a y , Chem. Be?., 9 5 , 2132 (1962).
